Melanocortin neurons are regulated by leptin and glucose, and other signals of nutritional state. These signals reach the neurons because of a leaky blood brain barrier at the median eminence. In obesity, it appears that leptin no longer regulates the melanocortin system. We will test the hypothesis that leptin is excluded from the brain because the blood brain barrier changes, and becomes less permeable at the median eminence of obese mice. We will also test if obesity causes a loss of glucose sensing in melanocortin neurons, and if this loss of glucose sensing causes changes in systemic glucose homeostasis. Specifically we will test if obesity induced melanocortin resistance to glucose releases the liver from a tonic inhibition, and allows the liver to secrete more glucose, requiring more insulin to control blood glucose levels in a normal range. We will test this hypothesis in obese glucose intolerant mice. Both of these hypotheses have the potential to generate new therapeutic strategies to treat obesity and early Type II diabetes.